In general, rifaximin is well known as a non-systemic antibiotic (<0.4%) characterized by activity against a broad spectrum of enteric bacterial pathogens and the delivery of high concentrations of antibiotic to the gastrointestinal tract.
The antibiotic rifaximin was discovered in 1980 and originally patented in Italy as IT Patent 1154655 granted on Jan. 21, 1987. The related U.S. Pat. No. 4,341,785 to Marchi et al. discloses imidazo-rifamicyn derivatives having antibacterial utility, and the related process for preparing it. The '785 patent also discloses a pharmaceutical antibacterial composition and a method of using it to treat antibacterial diseases of the gastrointestinal tract. A further patent, U.S. Pat. No. 4,557,866 to Cannata et al. discloses a process for the synthesis of pyrido-imidazo rifamycins. The process is described as an improvement over the '785 patent to Marchi in that the later process provides unsatisfactory yields from an industrial point of view.
Rifaximin is essentially a non-absorbable semi-synthetic antibiotic, related to rifamycin. The antimicrobial spectrum (in vitro) includes most gram-positive and gram-negative bacteria; and both aerobes and anaerobes.
It presents low risk for drug interactions (no effect on drugs metabolized by cytochrome p450 enzyme system) and about the same adverse properties as compared to a placebo. When ingested in tablet or pill form rifaximin is concentrated in the gastrointestinal tract and primarily excreted unchanged in the feces. It binds to the beta subunit of bacterial DNA-dependent RNA polymerase, which inhibits bacterial RNA synthesis. In contrast with other antibiotics, resistance to rifaximin is not plasmid-mediated but utilizes a chromosomal one-step alteration in the DNA-dependent RNA polymerase. In subjects using rifaximin no relevant resistance has been observed. Further, mutant resistant bacteria showed reduced viability and there is no systemic cross resistance for rifampin.
Since rifaximin is practically insoluble in water and is non absorbed (<0.4%) after oral administration, it can be used to treat localized diseases of the gastrointestinal tract. Rifaximin products specific for enteric pathogens of the gastro-intestinal tract are presently commercially marketed under various trade names—NORMIX® available from Alfa Wassermann S.p.A., Bologna, Italy; XIFAXAN® available from Salix Pharmaceutical, Raleigh, N.C.; REDACTIV® available from GlaxoSmithKline and FLONORM® from Schering-Plough. Since the solubility of rifaximin in water is approximately 1 μgmL3 the drug is virtually undissolved when traveling through the GI tract. The relative insolubility of rifaximin is thought to influence bacterial susceptibility and subsequent eradication due to the invasive nature of some enteric pathogens (e.g. Salmonella and Campylobacter). The relative insolubility of rifaximin also leads to its negligible systemic absorption. Rifaximin has been known to be effective for treating infections that are localized to the gut and is not known to be suitable for treating systemic infections caused by invasive organisms.
Rifaximin has been marketed in Italy since 1985 under the trademark NORMIX® for treating acute and chronic intestinal infections from gram-positive and gram-negative bacteria and as adjuvant in the therapy of the hyperammonoaemia. At present NORMIX® is marketed in the shape of pharmaceutical compositions, orally administrable, made by tablets or by granulates containing suitable pharmaceutically acceptable excipients together with rifaximin, but also other pharmaceutical forms orally administrable like capsules, sugar coated tablets and syrups can be used.
Xifaxan® is marketed in the United States and Canada and includes rifaximin as the active ingredient. The formulation is used in the treatment of travelers' diarrhea caused by the noninvasive strains of Escherichia coli. Xifaxan® is a non absorbable antiobiotic for gastrointestinal infections. Dr. Herbert DuPont, director of the Center for Infectious Diseases at the University of Texas, School of Public Health developed the drug for treatment of travelers' diarrhea. DuPont said “the drug is unique in that it remains in the gastrointestinal tract, compared with powerful antibiotics like Cipro that disperse throughout the body. This means the drug is less likely to breed resistant bacteria.” He said the antibiotic proved 85% effective in protecting US students who participated in a two-week study trip to Mexico, versus just 49% who didn't become sick on non-medicinal placebos. The drug has been found to have no significant side effects.
Products similar to NORMIX® and Xifaxan® are marketed in Mexico under the tradenames REDACTIV® and FLONORM®.
Other uses of rifaximin are disclosed in the following patents:
U.S. Pat. No. 5,886,002 to Ferrieri et al. describes use of rifaximin compositions in the treatment of diarrhea from cryptosporidiosis.
U.S. Pat. No. 5,352,679 to Ferrieri et al. describes use of rifaximin (INN) in formulations for treatment of gastric dyspepsia caused by Helicobacter pylori bacteria.
U.S. Pat. Nos. 5,314,904 and 6,140,355 both to Egidio et al. disclose compositions containing rifaximin for treatment of vaginal infections.
Known therapeutic uses of rifaximin, administered in a tablet form, include Clostridum difficile-associated diarrhea, Crohn's disease, Diverticular disease, Hepatic encephalopathy, Helicobacter pylori eradication, infectious diarrhea, irritable bowel syndrome, pouchitis, prophylaxis for GI surgery, small bowel overgrowth, traveler's diarrhea and ulcerative colitis. These therapies are directed to pediatric, adult and elderly subjects.
At present rifaximin has been studied and marketed only for the treatment of some kinds of bacterial infections located in the gastro-intestinal and reproductive tracts however prevention of aspiration pneumonia and sepsis has never been investigated.
Aspiration pneumonia is a lung infection/injury caused by aspiration of bacterial contents with or without chemical injury by gastric contents including acid or bile.
Pneumonia is a lung infection that can be caused by different types of microorganisms including bacteria, viruses, fungi, and parasites. Aspiration pneumonia is a lung infection/injury caused by aspiration of bacterial contents with or without chemical injury by gastric contents including acid or bile. Sepsis is a severe illness caused by overwhelming infection of the bloodstream by toxin-producing bacteria.
It has long been known that hospitalized patients, most significantly in intensive care unit settings, under acid suppression are at high risk for developing pneumonia due to bacterial colonization of the usually near sterile environments of the stomach and proximal small bowel. Critically ill patients are usually placed on acid suppression to prevent gastrointestinal bleeding from ulceration that occurs due to the stress of illness. The bacterial aggregation occurs primarily due to the loss of the acid in the stomach that normally protects the gut from bacteria, and/or the elevation of the pH of the stomach by continuous enteral feeding via nasogastric (NG) tubes or percutaneous endoscopic gastrotomy (PEG) or percutaneous endoscopic jejunostomy (PEJ) tubes. As a result, translocation of bacteria through the gut wall or direct reflux (aspiration) of the bacterial contents into the lung may occur, leading to pneumonia or sepsis.
It has also been recognized that healthy patients on strong acid suppression such as proton pump blockers or H2 blockers are at elevated risk for aspiration pneumonia, likely due to reflux and aspirations of gastric contents that contain elevated amounts of bacteria due to the acid suppression.
It has also been recognized that patients with impaired mental status especially patients undergoing sedation or anesthesia are at increased risk for aspiration pneumonia due to the loss of the protective gag reflux. As acid suppression is given to these patients to prevent chemical (acid) induced pneumonia the risks of bacterial pneumonia have increased.
PRILOSEC®, NEXIUM®, PREVACID®, PROTONIX®, ACIPHEX®, ZEGERID® are examples of commercially available proton pump blockers. Examples of commercially available H-2 BLOCKERS are ZANTAC®, TAGAMENT® and PEPCID®.
Antibiotics, such as rifaximin, that are non-absorbed by the body, have not been used to prevent a systemic illness such as pneumonia or sepsis. The present invention provides advantage in doing so such that there are no systemic side effects. The invention preparations which contain rifaximin directly target the cause of the pneumonia or sepsis without causing systemic harm to the person.
In addition, rifaximin is an antibiotic with a broad spectrum of in vitro bactericidal activity, and as resistance is not mediated through plasmids, it is not transferable to other bacteria in the hospital setting. If resistance did develop, the bacteria would be substantially less able to become pathogenic as they could not produce the RNA dependent proteins as effectively.
The non-absorbed antibiotic substantially reduces the degree of oral and upper gastrointestinal tract bacterial colonization, thus reducing the incidence of pneumonia and sepsis without inducing the complications and side effects a systemic antibiotic would have.
Accordingly the present invention is directed to use of rifaximin in preparations to prevent aspiration pneumonia and sepsis. The invention preparations are preferably provided for patients who have the normal protective mechanisms of the gut compromised by acid suppression or enteral feeding.
It is a general object of the invention to prevent aspiration pneumonia and or sepsis in patients under acid suppression by any type of antacids.
A further specific object of the invention is to prevent aspiration pneumonia and or sepsis in patients under acid suppression by proton pump blockers or H-2 blockers.
Another general object of the invention is to prevent aspiration pneumonia and or sepsis in patients on artificial enteral feeding tubes from developing these diseases.
Another specific object of the invention is to prevent aspiration pneumonia and or sepsis in patients on naso/oro gastric (NG) tubes or percutaneous endoscopic gastrotomy (PEG) or percutaneous endoscopic jejunostomy (PEJ) tubes.
Another specific object of the invention is to prevent aspiration pneumonia and/or sepsis in patients with impaired mental status, most specifically in those patients undergoing sedation or anesthesia.